Lysosome-Acidifying Nanoparticles Rescue A30P α-Synuclein Induced Neuronal Death in Cellular and Drosophila Models of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting over 10 million people worldwide. It is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α-synuclein (αSyn) in intracellular inclusions known as Lewy bodies. Emerging evidence links αSyn accumulation to impaired lysosomal acidification and defective autophagy-lysosomal degradation, which are central to disease progression. To address this lysosomal dysfunction, we engineered a novel type of lysosome-targeted acidic nanoparticles (AcNPs) based on a biodegradable copolymer, poly(ethylene tetrafluorosuccinate-co-succinate) (PEFSU). These nanomaterials were developed to locally acidify impaired lysosomes and restore their degradative capacity. We evaluated their therapeutic potential in two familial PD models: SH-SY5Y neuroblastoma cells overexpressing A30P αSyn and A30P αSyn transgenic Drosophila melanogaster. In vitro, AcNPs effectively restored lysosomal pH, enhanced autophagic clearance of αSyn, improved mitochondrial function, and rescued A30P αSyn-induced cytotoxicity. In vivo, AcNPs treatment reduced αSyn burden, preserved dopaminergic neurons, and improved motor function in flies. This study demonstrates the first application of lysosome-acidifying polymeric nanoparticles in familial PD models and highlights the promise of rationally engineered pH-modulating nanomaterials as therapeutic agents for PD and other neurodegenerative diseases driven by lysosomal dysfunction and protein aggregation.